We will investigate the neurobiology of preparatory set in order to isolate the cognitive components, and their neural substrates, of those brain switching mechanisms which enable humans to respond flexibly and efficiently to their environment. Reaction time (RT) experiments will be conducted in normal humans and neurological patients to separate the cortical and subcortical components of perceptual and motor preparatory set. The tasks are similar to those which have been employed in unit recordings in animal experiments for identifying selective enhancement related to preparatory set, so that the two strands of research may begin to converge. The perceptual set tasks involve a simple RT manual response on detecting a luminance changes in the visual field; the motor set tasks involve choice RT manual movements. For both tasks, preparatory set is induced by a preliminary visual cue which instructs the subject where to expect the target or which movement to prepare. Preparatory set is inferred, and its time course measured, on the basis of facilitation or inhibition in RT performance depending upon whether the cue correctly prepares the subject for the subsequent target. We will measure convert orienting in patients with progressive supranuclear palsy, and compare orienting into temporal and nasal hemifields in normal subjects, to test the hypotheses that midbrain centers are involved both in moving attention to exogenous signals, and in coordinating attention with eye movements. Experiments in patients with frontal and caudate lesions will test the hypothesis that these structures are involved in moving attention under endogenous control. Experiments in patients with thalamic lesions will test the hypothesis that the pulvinar is involved in engaging attention at a new location. Experiments in patients with Parkinson's disease, frontal lobe and cerebellar lesions will investigate the role of cortical and subcortical centers in mediating motor set. While the primary importance of this research lies in its potential for elucidating a fundamental problem in neurobiology, it also has potential clinical relevance as well. It may lead to more rational approaches to the rehabilitation of patients with attention and motor planning disorders due to neurological diseases.